uu.seUppsala University Publications
Change search
CiteExportLink to record
Permanent link

Direct link
Cite
Citation style
  • apa
  • ieee
  • modern-language-association
  • vancouver
  • Other style
More styles
Language
  • de-DE
  • en-GB
  • en-US
  • fi-FI
  • nn-NO
  • nn-NB
  • sv-SE
  • Other locale
More languages
Output format
  • html
  • text
  • asciidoc
  • rtf
Rapid palladium-catalyzed synthesis of esters from aryl halides utilizing Mo(CO)6 as a solid carbon monoxide source
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry.
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Organic Pharmaceutical Chemistry.
2003 (English)In: Journal of Combinatorial Chemistry, Vol. 5, no 4, 350-352 p.Article in journal (Refereed) Published
Place, publisher, year, edition, pages
2003. Vol. 5, no 4, 350-352 p.
National Category
Medical and Health Sciences
Identifiers
URN: urn:nbn:se:uu:diva-93926OAI: oai:DiVA.org:uu-93926DiVA: diva2:167568
Available from: 2006-01-13 Created: 2006-01-13 Last updated: 2013-07-04Bibliographically approved
In thesis
1. Design and Synthesis of Novel AT2 Receptor Ligands: From Peptides to Drug-Like Molecules
Open this publication in new window or tab >>Design and Synthesis of Novel AT2 Receptor Ligands: From Peptides to Drug-Like Molecules
2006 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

Many peptide receptors are of pharmaceutical interest and there is thus a need for new ligands for such receptors. Unfortunately, peptides are not suitable as orally administrated drugs since they are associated with poor absorption, rapid metabolism and low sub-receptor selectivity. One approach that should allow identification of more drug-like ligands is to use the structural information of the endogenous ligand to develop peptidomimetic compounds.

The main objective of the work described in this thesis was to convert angiotensin II (Ang II, Asp-Arg-Val-Tyr-Ile-His-Pro-Phe) to small drug-like compounds with retained bioactivity at the AT2 receptor. The study was performed step-wise via incorporation of well-defined secondary structure mimetics and repeated truncation of the peptide. Five scaffolds, comprising a benzene ring as a central element, suitable as a γ-turn or dipeptide mimetics were designed and synthesized. In order to decorate the scaffolds, a method of microwave-assisted alkoxycarbonylation was developed. After incorporation of the scaffolds into Ang II-related peptides or peptide fragments, the affinities for both the AT1 and the AT2 receptor were determined.

In the first series of ligands, two tyrosine-related scaffolds were introduced as γ-turn mimetics in Ang II. All five pseudopeptides exhibited good affinities for the AT2 receptor. One compound was chosen for functional studies and was shown to act as an AT2 receptor agonist. After truncation of Ang II it was shown that C-terminal pentapeptide analogs were AT2 receptor selective agonists. A series of pseudopeptides comprising tyrosine-related scaffolds, derived from the pentapeptides, displayed high AT2 receptor affinities. Two compounds had agonistic effect at the AT2 receptor.

This study revealed that the N-terminal part was of less importance while a C-terminal Ile residue was a key element for enhanced AT2 receptor affinity. In the final set of compounds, the peptide was truncated to tripeptide C-terminal fragments. After replacing His-Pro by a histidine-related scaffold small drug-like peptidomimetic compounds with nanomolar affinity for the AT2 receptor were identified.

Place, publisher, year, edition, pages
Uppsala: Acta Universitatis Upsaliensis, 2006. 73 p.
Series
Digital Comprehensive Summaries of Uppsala Dissertations from the Faculty of Pharmacy, ISSN 1651-6192 ; 26
Keyword
Pharmaceutical chemistry, angiotensin II, AT1, AT2, AT2 receptor agonist, peptidomimetics, γ-turn mimetics, carbonylation, microwave, molybdenum hexacarbonyl, Farmaceutisk kemi
National Category
Medicinal Chemistry
Identifiers
urn:nbn:se:uu:diva-6269 (URN)91-554-6438-6 (ISBN)
Public defence
2006-02-03, B42, Bio Medical Centre (BMC), Husargatan 3, Uppsala, 13:15 (English)
Opponent
Supervisors
Available from: 2006-01-13 Created: 2006-01-13 Last updated: 2013-09-04Bibliographically approved

Open Access in DiVA

No full text

Authority records BETA

Larhed, Mats

Search in DiVA

By author/editor
Larhed, Mats
By organisation
Department of Medicinal ChemistryOrganic Pharmaceutical Chemistry
Medical and Health Sciences

Search outside of DiVA

GoogleGoogle Scholar

urn-nbn

Altmetric score

urn-nbn
Total: 520 hits
CiteExportLink to record
Permanent link

Direct link
Cite
Citation style
  • apa
  • ieee
  • modern-language-association
  • vancouver
  • Other style
More styles
Language
  • de-DE
  • en-GB
  • en-US
  • fi-FI
  • nn-NO
  • nn-NB
  • sv-SE
  • Other locale
More languages
Output format
  • html
  • text
  • asciidoc
  • rtf